The atomistic level structure for the activated human κ-opioid receptor bound to the full Gi protein and the MP1104 agonist
Abstract
The kappa opioid receptor (κOR) is an important target for pain therapeutics to reduce depression and other harmful side effects of existing medications. The analgesic activity is mediated by κOR signaling through the adenylyl cyclase-inhibitory family of Gi protein. Here, we report the three-dimensional (3D) structure for the active state of human κOR complexed with both heterotrimeric Gi protein and MP1104 agonist. This structure resulted from long molecular dynamics (MD) and metadynamics (metaMD) simulations starting from the 3.1-Å X-ray structure of κOR–MP1104 after replacing the nanobody with the activated Gi protein and from the 3.5-Å cryo-EM structure of μOR–Gi complex after replacing the 168 missing residues. Using MD and metaMD we discovered interactions to the Gi protein with strong anchors to two intracellular loops and transmembrane helix 6 of the κOR. These anchors strengthen the binding, contributing to a contraction in the binding pocket but an expansion in the cytoplasmic region of κOR to accommodate G protein. These remarkable changes in κOR structure reveal that the anchors are essential for activation.
Additional Information
© 2020 National Academy of Sciences. Published under the PNAS license. Contributed by William A. Goddard III, January 22, 2020 (sent for review June 11, 2019; reviewed by Krzysztof Palczewski and Nagarajan Vaidehi). PNAS first published March 3, 2020. This work was supported by the Gwangju Institute of Science and Technology (GIST)–Caltech Research Collaboration Project through a grant provided by GIST for 2016–2018. It was also funded by grants from the China Scholarship Council and by gifts to the Materials and Process Simulation Center. The computational resources were provided by a Defense-University Research Instrumentation Project-Office of Naval Research grant to W.A.G. Author contributions: A.M. and W.A.G. designed research; A.M. performed research; A.M., S.-K.K., and W.A.G. analyzed data; and A.M., S.-K.K., and W.A.G. wrote the paper. Reviewers: K.P., University of California, Irvine; and N.V., City Of Hope National Medical Center. The authors declare no competing interest. Data deposition: Our optimized structure has been deposited in GitHub, https://github.com/amafi-gpcr/Kappa-Opioid-Receptor-Gi-Protein-MP1104-agonist-Complex-PNAS-2020. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1910006117/-/DCSupplemental.Attached Files
Published - 5836.full.pdf
Supplemental Material - pnas.1910006117.sapp.pdf
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Additional details
- PMCID
- PMC7084096
- Eprint ID
- 101696
- DOI
- 10.1073/pnas.1910006117
- Resolver ID
- CaltechAUTHORS:20200304-085059535
- Gwangju Institute of Science and Technology
- China Scholarship Council
- Caltech Materials and Process Simulation Center (MSC)
- Office of Naval Research (ONR)
- Created
-
2020-03-04Created from EPrint's datestamp field
- Updated
-
2021-11-16Created from EPrint's last_modified field
- Other Numbering System Name
- WAG
- Other Numbering System Identifier
- 1371